PROJECT SUMMARY Achieving functional ambulation post stroke continues to be a challenge for stroke survivors, clinicians and researchers. The proposed study builds on our earlier R01 where we successfully examined the feasibility of a clinically implementable walking program which involves high intensity speed-based treadmill training (HIISTT) in combination with cortical priming to improve walking speed of individuals with stroke. Cortical priming has emerged as a promising adjuvant to enhance the outcomes of motor training. Our research team has pioneered and successfully developed neuromodulation techniques for the lower limb motor cortex using non-invasive transcranial direct current stimulation (tDCS) and ankle motor skill training. In this renewal application, our goal is to quantify the effectiveness of 36 sessions of cortical priming plus HIISTT intervention in comparison to sham priming plus HIISTT. Outcome measures will include gait variables, balance, aerobic capacity, quality of life, neurophysiological measures of descending and interhemispheric corticomotor excitability measured with transcranial magnetic stimulation (TMS), and changes in serum BDNF before, immediately after and 3-months post training. There has been a growing interest in understanding responsiveness to training to personalize stroke rehabilitation. We aim to understand variability in responsiveness to training using patient-specific parameters such as participant demographics, neurophysiological measures and the presence of genetic variations such as brain derived neurotrophic factor (BDNF) polymorphism. With our innovative mechanistic approach to enhance walking recovery, we seek to optimize gait rehabilitation post stroke and characterize relationships between neural mechanisms, motor function and genetic variations. Improved gait will enable stroke survivors to be more independent in the community and advance their quality of life, which is highly relevant to the mission of the NIH.